Dr. Maureen Hanson, a professor of molecular biology and genetics at Cornell University and member of Solve’s Research Advisory Council, specializes in understanding the molecular nature of ME/CFS. ME/CFS has affected Dr. Hanson’s own family, and she is an important ME/CFS researcher and strong patient advocate. Recently, Dr. Hanson’s team published a study in Clinical and Translational Medicine comparing how ME/CFS and exercise relate to extracellular vesicles in men.
Extracellular vesicles are small, membraned droplets that are released from cells and that can contain many molecules that affect other cells or tissues. After a person exercises, for example, cells may release into the blood extracellular vesicles with molecules to help repair damaged tissues or to improve how tissues use energy while recovering from physical exertion. In this study, Dr. Hanson’s team compared extracellular vesicles in blood samples from healthy men with those in samples from men with ME/CFS. For both groups of men, the team collected samples before exercise and after. They then looked for differences in extracellular vesicle proteins among these groups and whether any differences related to severity of ME/CFS symptoms, like post-exertional malaise or unrefreshing sleep.
The team found levels of many extracellular vesicle proteins from healthy men differed from those from men with ME/CFS. Even before exercise, some of these differences suggested that men with ME/CFS have problems with blood clotting; immune functions (especially with neutrophils, important for early immunological defenses, and with complement proteins, important for targeting infectious agents); making and breaking down proteins; metabolism; and oxidative stress. The differences in complement proteins got worse soon after exercise, possibly exacerbating post-exertional malaise. Other differences appearing soon after exercise suggested that the men with ME/CFS were improperly recovering from exercise regarding how their mitochondria processed energy and how they regulated coagulation (blood clotting).
Severity of post-exertional malaise (PEM) correlated with differences in extracellular vesicle proteins related to the endoplasmic reticulum stress response and to protein folding. In other words, the men in whom levels of these extracellular vesicle proteins changed the most also had the most severe post-exertional malaise. And severity of unrefreshing sleep correlated with differences in extracellular vesicle proteins related to cell signaling, metabolism, and protein folding. These results suggested that men with ME/CFS may experience symptoms of post-exertional malaise and unrefreshing sleep after exercise because of problems with endoplasmic reticulum stress response, with protein folding, and with using energy to recover from physical stress.
Importantly, while the levels of some extracellular vesicle proteins (like those related to blood acidity, blood flow, and blood oxygen transport) after exercise correlated with exercise performance in healthy men, they did not correlate in men with ME/CFS. This supports the idea that men with ME/CFS no longer physiologically respond to exercise as they should, hampering their recovery from the stress of exercise.
Overall, these results are important because they suggest people with ME/CFS and post-exertional malaise or unrefreshing sleep may benefit from drugs that control complement; that help proteins fold properly; that lower stress on the endoplasmic reticulum; or that help tissues use energy better when recovering from exercise.
The authors noted several ways to better study how differences in extracellular vesicles are related to severity of ME/CFS symptoms. First, future studies should consider more participants; this study compared only ten men with ME/CFS with a dozen healthy men. Second, future studies should address differences in extracellular vesicle proteins between men and women; and differences in extracellular vesicle proteins among men with even more severe symptoms than the men studied here.
This study excluded men with especially severe symptoms because these people would have struggled with exercising. The authors also recommended that future studies should remove platelets from blood plasma samples to reduce levels of extracellular vesicles from platelets (as opposed to extracellular vesicles from cells).
Why This Study Matters to the Patient Community:
- Suggests processes whose dysregulation may contribute to ME/CFS symptoms after exercise: Finds changed levels of proteins involved in endoplasmic reticulum responses, metabolism, and protein folding to correlate with symptom severity.
- Lays the Groundwork for Targeted Treatments: Suggests drugs targeting these processes and other processes (like complement) may reduce post-exertional malaise and unrefreshing sleep for some patients.
- Advances Diagnostic Tools: Shows extracellular vesicle proteins are useful and convenient biomarkers for some exercise-related symptoms of ME/CFS.
- Relevant for key symptoms of ME/CFS: Focuses on two hallmark symptoms of ME/CFS—post-exertional malaise and unrefreshing sleep.
Read the study, “Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome,” here.
